Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women.

To determine the safety of 2 candidate vaccines against human immunodeficiency virus type 1 (HIV-1), a randomized, placebo-controlled, multicenter trial compared low, medium, and high doses of the vaccines or an adjuvant among infants born to HIV-infected women. No local or systemic reactions of grade 2 or greater were reported 48 h after the subjects underwent immunization. Grade 3 or 4 chemistry toxicities occurred in 5 (3%) and grade 3 or 4 hematologic toxicities in 17 (11%) of 154 vaccinated subjects (not significantly different from 29 adjuvant recipients). CD4(+) cell percentages of < or = 20% occurred at least once in 9 vaccinated subjects and 1 control subject. Sustained CD4(+) cell percentages of < or = 20% occurred in 4 HIV-infected children. Fourteen infants (8%) were confirmed to be HIV-infected; median CD4(+) cell counts among these children were 2074, 1674, 1584, and 821 cells/mm(3) at birth and weeks 24, 52, and 104, respectively. Thus, both vaccines were safe and well tolerated in neonates, and there was no evidence of accelerated immunologic decline in HIV-infected infants.     

Induction of anti-human immunodeficiency virus (HIV) neutralizing antibodies in rabbits immunized with recombinant HIV--hepatitis B surface antigen particles.

Fragments of the human immunodeficiency virus (HIV) envelope coding region have been fused with the hepatitis B virus envelope middle protein. In this system, HIV antigenic determinants are exposed at the surface of a highly antigenic structure, the hepatitis B surface antigen particle. Immunization of rabbits with these particles elicited antibodies directed against both parts of the hybrid protein. One of the rabbit antisera not only exhibited a neutralizing effect on the original HIV1 isolate but also on a divergent Zairian isolate. The HIV sequence in this recombinant is 84 amino acids long and contains conserved and variable domains and a region critical for interaction with the CD4 receptor. Such recombinant antigens could be primary elements in the design of a polyvalent vaccine.     

Analysis of human serum antibodies to human immunodeficiency virus (HIV) using recombinant ENV and GAG antigens

Recombinant proteins representing gag and env amino acid sequences of the Human Immunodeficiency Virus (HIV) (HTLV-IIIb) were produced in Escherichia coli and used to analyze sera for the presence of antibodies to HIV. ENV-9 is a protein representing the carboxy terminus of gp120 and part of gp41 which is highly immunoreactive. GAG-1 represents 83% and GAG-55 100% of the amino acids of the gag open reading frame. The purified proteins allow sensitive detection by enzyme linked immunosorbent assay (ELISA) of antibodies directed against either env or gag of HIV. We have determined the reactivity of sera from several HIV exposed individuals, either form high risk populations or with clinically defined conditions, in the ENV-9, GAG-55, and GAG-1 assays and found that two major seropositive groups are observed. The quantitative analysis of sera with env and gag antigens by ELISA showed AIDS patients had very low gag reactivity while retaining high env reactivity. Results obtained with authentic p24 viral protein in both ELISA and radioimmunoassay correlated to those from the GAG-55 ELISA. This correlation and the analysis of sera with both the ENV and GAG ELISAs indicate that the antibodies reactive to gag are specifically affected relative to env reactivity and that different levels of antibodies to separate viral components in these sera may correlate with disease state.     

Monoclonal antibodies against human immunodeficiency virus (HIV) type 2 core proteins: cross-reactivity with HIV type 1 and simian immunodeficiency virus.

Four mouse monoclonal antibodies were developed after immunization with one human immunodeficiency virus (HIV) type 2 isolate and were tested for reactivity with different HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates in an immunofluorescence assay and by immunological blot analysis. One of them, an anti-capsid (p24) antibody, called R1C7, reacted with all HIV-1, HIV-2, and SIV isolates tested, thus identifying an epitope shared by all HIV and SIV. Another anti-capsid antibody, named A4F6, reacted with three HIV-2 isolates (HIV-2NIH-Z, LAV-2Rod, and LK001 ST9), some SIV isolates (STLV-IIIAGM, SIV-251, and SIV-309), but no HIV-1 isolates. Two anti-matrix (p16) antibodies, named R5C4 and R5F6, reacted strongly only with the HIV-2 isolates. The use of these monoclonal antibodies for rapid discrimination and identification of acquired immunodeficiency syndrome-related retroviruses is discussed.     

Platelet antibodies in serum of patients with human immunodeficiency virus (HIV) infection

Between 10 and 15% of human immunodeficiency virus (HIV) seropositive individuals develop an immune thrombocytopenic purpura; however, the mechanism involved in platelet destruction is not yet established. In the present work, we have analyzed 208 sera from HIV seropositive individuals, including 85 thrombocytopenic patients, for the presence of autoantibodies against platelet proteins by using the Western blot technique. Our results indicate that: (1) antibodies against platelet proteins were found in 8 of 123 (6.5%) nonthrombocytopenic patients, as compared with 17 of 85 (20%) of thrombocytopenic patients (p less than 0.03); (2) these antibodies appeared to be more frequently found in advanced stages of disease (p less than 0.02); (3) the reactivity of positive sera with antigenic determinants implicated several distinct platelet proteins; (4) antigens thus recognized are unrelated to the major membrane glycoproteins IIb and IIIa, as well as absent in vero cells and trypsin-sensitive cells. Such results underscore the difficulties in establishing the mechanisms involved in platelet destruction during HIV infection.     

Production and of monoclonal antibodies to simian immunodeficiency virus envelope glycoproteins.

Eighteen monoclonal antibodies (MAb) to simian immunodeficiency virus (SIV) envelope have been characterized. All MAb were shown to bind to viral antigens on the surface of unfixed SIV-infected cells and to precipitate surface glycoproteins of SIVmac251. In Western blot 11 MAb bound to gp160 and gp120, five bound to gp160 and the transmembrane protein gp41 and two MAb did not react with denatured antigen. Preliminary competition assays identified the existence of six competition groups; two groups were within gp41 and four were within gp120. Of the latter four groups, three contained MAb with neutralizing activity. Two of the neutralizing MAb (KK5 and KK9) did not react with denatured antigen in Western blot suggesting that they may recognize conformational epitopes. Enzyme-linked immunosorbent-assay titres of MAb against SIVmac251 ranged from 10(2.4) to 10(5.6) and although similar titres were obtained with some MAb against other SIV and HIV antigens, the presence of isolate specific and shared group epitopes was demonstrated.     

Enhanced immunity to human immunodeficiency virus (HIV) envelope elicited by a combined vaccine regimen consisting of priming with a vaccinia recombinant expressing HIV envelope and boosting with gp160 protein.

Transmission studies have suggested that an optimal human immunodeficiency virus type 1 (HIV-1) vaccine should induce both neutralizing antibodies and cytolytic T cells to eliminate free virus and infected cells. A phase I trial in healthy HIV-1-seronegative persons was conducted with a combination HIV-1 vaccine regimen (strain IIIB) consisting of priming with a recombinant vaccinia (vac/env) virus expressing HIV-1 envelope and boosting with a gp160 glycoprotein derived from a recombinant baculovirus (rgp160). T-cell and antibody responses detected after immunization with either vac/env alone or rgp160 alone were generally of low magnitude and transient, and no subject developed neutralizing antibodies. In contrast, recipients of the combination regimen demonstrated in vitro T-cell proliferative responses to homologous HIV-1 antigens that were 3- to 10-fold higher than responses with either vaccine alone, and these responses were sustained for > 18 months in 75% of recipients. Moreover, both CD8+ and CD4+ cytolytic T cells were detected. Antibody responses (titer, 1:800 to 1:102,400) to homologous HIV envelope developed in all recipients of the combination regimen, and neutralizing antibodies were detected in 7 of 13. Thus, immunization with a live virus vaccine followed by boosting with a soluble protein offers promise for inducing the broad immunity needed in an HIV vaccine.     

AIDS and antibodies to human immunodeficiency virus (HIV) in children and their families

Infection with human immunodeficiency virus (HIV, previously known as HTLV-III/LAV) documented by a sensitive, specific immunoblotting (western blot) technique is described in 14 children with symptoms of AIDS or AIDS-related complex. For serodiagnosis of HIV infection, immunoblots blocked with milk were more sensitive than enzyme-linked immunosorbent assays or immunoblots blocked with gelatin. One or both parents of 13 of these children abused intravenous drugs. Sixteen of 17 parents of the affected children but only one of eight siblings living in the same household were positive for antibody to HIV. All siblings had experienced infection and acquired antibodies to Epstein-Barr virus, which is thought to spread by saliva. In contrast to their HIV-infected parents, children with AIDS or AIDS-related complex were less likely to have decreased numbers of circulating T4 cells, and their sera recognized fewer HIV polypeptides on western blots.     

Dendritic cells and the promise of therapeutic vaccines for human immunodeficiency virus (HIV)-1

Treatment of human immunodeficiency virus (HIV)-1 infection with potent antiretroviral medications has provided considerable clinical benefit. However because of the limitations of current therapy, innovative approaches are needed to better control HIV-1 infection. Several studies have suggested that robust CD4+ T helper and CD8+ T cell responses may contribute to the immunologic control of HIV-1 infection in certain individuals. Most chronically infected patients, however, cannot control the infection and may benefit from stimulation of cellular immunity with immunotherapy. Dendritic cells (DCs) are potent professional antigen-presenting cells (APCs) and have a central role in directing the adaptive immune response to pathogens. The ability of DCs to stimulate naive T cells has long been thought to be crucial in initiating an effective immune response. As DCs are uniquely situated at the interface between the innate and adaptive immune systems, they are currently under intense scrutiny as potential adjuvants for vaccines in many clinical settings. Studies in healthy volunteers and patients with cancer have shown that antigen-pulsed DCs can boost both CD8+ and CD4+ T cell responses in vivo. Based on these promising findings, ex vivo antigen-pulsed DCs are being actively investigated in studies aimed at developing a therapeutic vaccine for individuals with HIV-1 infection.     

The influence of human immunodeficiency virus (HIV) infection on antibody responses to influenza vaccines

STUDY OBJECTIVE: To ascertain whether subjects infected with human immunodeficiency virus (HIV) generally develop protective hemagglutination inhibition antibody responses to inactivated influenza vaccines. DESIGN: Prospective study of 104 persons before and after immunization. SETTING: Outpatient clinic and hospital ward. PATIENTS: Persons with the acquired immunodeficiency syndrome (AIDS) (n = 25), AIDS-related complex (n = 14), and HIV-seropositive men with only lymphadenopathy or no symptoms (n = 27). Controls were HIV-seronegative homosexual men (n = 22) and HIV-seronegative heterosexuals (n = 16). INTERVENTIONS: Subjects were immunized with inactivated vaccines containing 15 micrograms of each of the following influenza virus hemagglutinins: A/Taiwan/1/86 (HINI), A/Mississippi/1/85 (H3N2), A/Chile/1/83 (HINI), and B/Ann Arbor/1/86. MEASUREMENTS AND MAIN RESULTS: Fourfold or greater antibody responses occurred less frequently in subjects with HIV infections than in HIV-seronegative controls. Protective levels (1:64 or greater) of hemagglutination inhibition antibodies were attained by 94% to 100% of HIV-seronegative controls, 52% to 89% of HIV-seropositive asymptomatic subjects, and 13% to 50% of subjects with AIDS or AIDS-related complex. No increase in the prevalence or level of serum HIV p24 antigen or clinical deterioration was detected among HIV-infected persons after influenza immunization. CONCLUSIONS: Because of the poor antibody responses to influenza vaccines among HIV-infected subjects, even in many with no or minimal symptoms, alternative strategies for preventing influenza, such as booster doses of influenza vaccine, prophylaxis with amantidine, or both should be considered.     

Human immunodeficiency virus (HIV) in developing countries

The human immunodeficiency virus (HIV) is causing the most destructive epidemic of recent times, having been responsible for the deaths of more than 25 million people since it was first recognised in 1981. This global epidemic remains out of control, with reported figures for 2005 of 40 million people infected with HIV. During 2005 there were 4.9 million new infections, showing that transmission is not being prevented, and there were 3.1 million deaths from the acquired immunodeficiency syndrome (AIDS), reflecting the lack of a definitive cure and the limited access to suppressive antiretroviral treatment in the developing countries that are most severely affected. The current state of the epidemic and the response to date are here reviewed. Present and future opportunities for prevention, treatment and surveillance are discussed, with particular reference to progress towards an HIV vaccine, the expansion of the provision of highly active antiretroviral therapy, and the need to focus control programmes on HIV as an infectious disease, rather than as a development issue.     

Comparison of linear antigenic sites in the envelope proteins of human immunodeficiency virus (HIV) type 2 and type 1.

The occurrence of dominant linear antigenic sites in the envelope glycoproteins of human immunodeficiency virus type 2 (HIV-2) was evaluated. Twenty-five peptides representing different regions of HIV-2, strain SBL-6669, were synthesized. For comparison the corresponding peptides of HIV-1, strain BRU, were also prepared. The peptides were tested in enzyme-linked immunosorbent assay (ELISA) with human sera from individuals with proven HIV-1 or HIV-2 infection and simian sera from animals infected with HIV-2 or simian immunodeficiency virus of sooty mangabay monkey origin (SIVsm). Four major antigenic regions were identified. Peptides representing parts or the whole V3 (neutralizing loop) region and an additional stretch of amino acids located at the carboxy terminal of this region showed considerable reactivity. This reaction was predominantly type specific, but some heterotypic reactivity was also seen. Peptides representing the carboxy terminal 21 amino acids of the V3 region of the type-related viruses HIV-2 and SIVsm allowed selective identification of strain-specific antibodies. A second major antigenic region was found close to the carboxy terminal end of the large glycoproteins. This region was cross-reactive between the two types. The two additional dominating antigenic regions were located in the amino terminal region of the transmembrane glycoprotein. One region has previously been shown to be a uniquely antigenic type-specific site. The other region was also type-specific, but was identified only in HIV-2, amino acids Glu634-Lys649. Excellent facilities are available for the design of not only type-unique site-specific serological tests but potentially also type-cross-reactive and strain-specific assays.     

Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients.

Thirty of 81 consecutive HIV antibody positive patients referred with non-cryptosporidial diarrhoea had no potential infectious cause; most had AIDS related complex rather than the full blown syndrome. Opportunistic infections with cytomegalovirus (CMV), mycobacterium avium-intracellulare (MAI), and herpes simplex virus (HSV), which allowed a diagnosis of AIDS to be made, were found in 19 patients and were the presenting features of AIDS in five. Other potential pathogenic species included entamoeba, giardia, campylobacter, and salmonella (without septicaemia). Cytomegalovirus infection was often accompanied by abdominal pain. Severe weight loss (greater than 10 kg) at presentation was found in patients with CMV infection and MAI. Bloody diarrhoea was confined to the group with HSV procitis. Malignant causes of diarrhoea were rare. Two patients developed a squamous carcinoma of the anorectal margin and one a non-Hodgkin's lymphoma. In only two of 12 patients who had Kaposi's sarcoma was this considered as a cause of diarrhoea. Rigid sigmoidoscopy showed macroscopic abnormalities in over a third (32) of the 81 patients with non-cryptosporidial diarrhoea. Most commonly this was severe inflammation (17) or discrete ulceration (four) [three of whom had CMV colitis]. Kaposi's sarcoma was identified in 11 patients. Non-specific inflammation was seen histologically in 40 of the 60 patients with no sigmoidoscopic inflammatory changes. Barium enema only revealed an abnormality in a minority of the patients and a colonoscopy only revealed information additional to rigid sigmoidoscopy in two patients--one with CMV ulcers in the transverse colon and the other with evidence of Kaposi's sarcoma not seen in the rectum. Ten patients had a rectal biopsy examined by electron microscopy as no infective cause of diarrhoea was uncovered. In four of these microtubular structures which are commonly seen in viral infections were found and two had prelymphomatous changes and in one of these frank lymphoma has developed. We recommend multiple stool analysis, sigmoidoscopy and rectal biopsy as the initial investigations in these patients reserving tests of malabsorption, colonoscopy, and barium enema for the small number of more difficult cases.     

Defining human immunodeficiency virus (HIV) type 1 immunotypes with six human monoclonal antibodies

Studies of HIV-1 immunological relatedness have revealed that genetic diversity does not parallel antigenic diversity and have recently shown that HIV-1 strains from different geographic regions from around the world can be grouped into a small number of immunologically defined groups (immunotypes). Previously, the binding patterns of 28 monoclonal antibodies (mAbs) (specific for V3 and C5 of gp120 and cluster I of gp41) with 26 HIV-1 virions obtained globally were determined in a virus binding assay. Analysis of the binding patterns of these 728 mAb/virus combinations now reveals that a particular subset containing six of the 28 mAbs can correctly immunotype 24 of the 26 isolates (92%) into three immunotypes. Like the original panel of mAbs, the subset of six mAbs identified was directed against epitopes in the V3 and C5 regions of gp 120 as well as cluster I of gp41. The binding patterns ("profiles") of these six mAbs with 24 additional HIV-1 virions from Cameroon confirmed that epitopes in V3 and C5 of gp120 and cluster I of gp41 are well exposed on these viruses. Multivariate analysis of the binding patterns of these six mAbs with all 50 viruses (26 obtained globally and 24 obtained from Cameroon) indicates that the viruses from Cameroon have binding profiles similar to viruses from the rest of the world and can be classified into the same three immunotypes that were previously described. This study suggests that a vaccine against HIV-1 need not be based on geographic origin of the virus or on clade, but may better be based on antigenic properties that classify the plethora of different HIV-1 viruses into immunologically defined groups.     

Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia

Human immunodeficiency virus (HIV) infection of the nervous system is unique when compared with other viral encephalitides. Neuronal cell loss occurs in the absence of neuronal infection. Viral proteins, termed "virotoxins," are released from the infected glial cells that initiate a cascade of positive feedback loops by activating uninfected microglial cells and astrocytes. These activated cells release a variety of toxic substances that result in neuronal dysfunction and cell loss. The virotoxins act by a hit and run phenomenon. Thus, a transient exposure to the proteins initiates the neurotoxic cascade. High concentrations of these proteins likely occur in tight extracellular spaces where they may cause direct neurotoxicity as well. The emerging concepts in viral protein-induced neurotoxicity are reviewed as are the neurotoxic potential of each protein. Future therapeutic strategies must target common mechanisms such as oxidative stress and dysregulation of intracellular calcium involved in virotoxin-mediated neurotoxicity.     

Human immunodeficiency virus (HIV) infection and the kidney

Since the first report on the acquired immunodeficiency syndrome (AIDS) in 1981, organ involvement of AIDS has increased. We discuss the effect of human immunodeficiency virus (HIV) infection, the causative agent of AIDS, on the field of nephrology. Hyponatremia, the commonest fluid and electrolyte abnormality, is caused by various pathophysiologic mechanisms, including adrenal insufficiency. The renal parenchymal complications are diverse, but a new entity, HIV-associated nephropathy, is becoming recognized because of its characteristic clinical and pathologic features, including the fact that it causes irreversible renal failure. HIV infection in patients with end-stage renal failure, both before and after initiation of maintenance dialysis, is a significant problem. The present methods of preventing spread of virus in dialysis units seem successful. Few patients who are infected with HIV or who have AIDS have had renal transplantation, although unsuspected viral infection of cadaveric organs remains a concern.     

Human immunodeficiency virus (HIV) and the occupational physician

This paper reviews the issues concerning occupational physicians in relation to HIV infection and AIDS, including the epidemiology and the indications for HIV antibody testing in employment. The role of the occupational physician in caring for employees infected with HIV and in educating the workforce is discussed.